Plasma membranes separate the highly specialized interior of each cell from the milieu which bathes all cells. Because the red cell is in motion and called upon to change shape as it traverses orifices and channels smaller than itself, the red cell membrane must, in addition, possess an unusual ability to undergo deformation. Membranes are not static structural barriers but rather undergo dynamic interaction with their environment. Thus, for example, lipids, which constitute approximately half of the plasma membrane by weight, exchange to varying degrees with their counterparts in plasma lipoproteins. A number of laboratories, including that of the principal investigator, have studied disease states in which abnormalities of red cell membrane lipids lead to distortions of membrane architecture and cell function and cause premature cell destruction in vivo. These changes are often the secondary result of a primary abnormality of the plasma environment. The broad objective of this project is to study the synthesis and maturation of red cell membrane lipids, their role in the barrier and transport functions of the cell, their interaction with substances in their environment such as lipoproteins, steroid hormones, and bile acids, and their abnormalities under pathologic conditions. This will be approached primarily through the study of human diseases in which red cell membranes and serum lipids are altered and secondarily in animal models of these diseases and under conditions contrived in vitro. Inherent in this is an analysis in depth of the functional role of various structural and molecular components of the red cell membrane.